1. Field of the Invention
This invention relates to novel pharmaceutical compositions containing as an active ingredient compounds which produce antipsychotic activity predicted to be essentially free of extrapyramidal symptoms (EPS) and to a method of producing antipsychotic activity expected to be essentially free of EPS which comprises administering non-toxic, effective quantities of these compounds to an animal. EPS are some of the most undesirable and common side effects produced by antipsychotic or neuroleptic drugs. The compounds which are the active ingredients used in the composition and methods of this invention have a profile of binding to serotonin (5-HT.sub.2), dopamine (D-2), and sigma receptors suggestive of antipsychotic activity with essentially no liability to produce EPS. By virtue of their 5-HT.sub.2 antagonist activity these compounds also are useful in treating other disorders of the cardiovascular and central nervous systems.
2. Description of Related Information
A variety of evidence [I. Creese, D. R. Burt, and S. H. Snyder, Science, 192, 481 (1976); E. F. Domino and B. Kovacic, Mod. Problems Pharmacopsychiat. 21, 21 (1983); A. J. Stoessl, C. T. Dourish, and S. D. Iverson, Psychopharmacol., 98, 372 (1989)] suggests that EPS associated with traditional antipsychotic agents results from the antagonist activity of these drugs at D-2 dopamine receptors. Recent studies have shown that classical antipsychotic drugs including chlorpromazine and haloperidol, bind to both dopamine D-2 and sigma receptors and that their antipsychotic actions may result from blockade at both of these classes of receptors which are associated with production of psychoses [S. H. Snyder and B. L. Largent, J. Neuropsychol. 1, 7 (1988)]. In animals, antipsychotic-like actions without concomitant effects associated with EPS have been observed with sigma ligands that lack significant affinity for dopamine D-2 receptors [W. Guy, G. Manon and W. H. Wilson, Drug Dev. Res. 3, (1983); D. Taylor and J. Dekleva, Drug Dev. Res. 11, 65 (1987)]. Antipsychotic activity with minimal EPS liability has also been noted in schizophrenic patients treated with a potent serotonin 5-HT.sub.2 receptor antagonist [R. Axelsson, A. Nilsson, E. Christensson and A. Bjork, Psychopharmacol. 104, 287-292 (1991)] or a mixed 5-HT.sub.2 and D-2 antagonist [J. F. Castelas et al. Schizophrenia Res. 2, 411-415, (1989)].
U.S. Pat. No. 4,360,673 to Berger et al. describes a series of 5-phenyl-1,3-alkano-1,2,3,4,4a,9b-hexahydropyrido[4,3-b]indoles which are useful as antidepressants but are not stated to be useful as antipsychotics.
U.S. Pat. No. 4,174,453 to Beger et al. discloses a series of trans hexahydropyridoindoles having various utilities including as antipsychotics and anxiolytics.
Welch et al. [J. Med. Chem. 23, 949-952 1980] reported that 4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxy-bu tyl]-2,3,4,4a,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride is a potent neuroleptic which acts by blocking dopamine receptors.
Harbert et al. [J. Med. Chem. 23, 635-643 (1980)] described various 5-aryltetrahydro-.gamma.-carbolines which are effective neuroleptics. The mechanism of action of these compounds was thought to be blockade of central dopamine receptors.
Harbert et al. [Mol. Pharm. 17, 38-42 (1980)] also described the conformational requirements for interaction with dopamine receptors for a series of 5-aryltetrahydro-.gamma.-carboline compounds.
Abou-Gharbia et al. [J. Med. Chem. 30, 1818-1823] reported that certain .gamma.-carbolines have antipsychotic activity.